DESCRIPTION (Applicant's abstract): The long-range goals of the PI are to evaluate the mechanisms that regulate blood flow delivery in heart failure. The short-range goals are to determine: 1) the interstitial metabolites that may evoke the muscle metaboreflex in heart failure, and 2) the effects of exercise conditioning on reflex responses to exercise in heart failure. Recent work from our laboratory has suggested that the muscle metaboreflex is engaged at low levels of rhythmic forearm exercise in heart failure patients. This premature reflex engagement was associated with increased sympathetic drive directed to inactive skeletal muscle. To date no one has characterized the interstitial concentrations of the many muscle metabolites that may be responsible for engaging this reflex in normal subjects and those with heart failure. We have begun using the microdialysis method to directly determine interstitial concentrations of multiple potential metaboreceptor stimulants in humans. We have spent a great deal of effort over the last few years modifying microdialysis methods so that we can now measure lactate, phosphate, adenosine, potassium and hydrogen ion in the interstitium of resting and exercising skeletal muscle. In this proposal we will utilize this method during rhythmic quadriceps contractions in subjects with heart failure and in aged-matched and young controls as we simultaneously measure opposite leg muscle sympathetic nerve activity (MSNA). We hypothesize that K+ and phosphate will correlate best with MSNA. We will then examine the effects of quadriceps muscle conditioning on muscle metaboreflex activity. In separate studies, we will compare the effects of ischemic and non- ischemic conditioning on the muscle reflex in the three subject groups discussed above. We speculate that conditioning will increase limb blood flow, reduce metabolite production and in the process reduce MSNA responses to quadriceps contractions more in heart failure subjects than in controls. We speculate that ischemic forearm training will serve as a potent stimulus to attenuate MSNA in the peroneal nerve and vasoconstrictor influences in the exercising forearm. Novel components of the work described include the use of multiple state of the art human investigative techniques including microdialysis, peroneal nerve recordings of sympathetic traffic, Doppler flow measurements, 31P NMR spectroscopy, and the use of ischemic and non-ischemic exercise conditioning paradigms. To our knowledge studies such as these have not been previously performed.